The ultimate objective of this program is to determine if there may be detrimental health effect associated with human use of certain drugs of abuse because of their retention in the body as fatty acid conjugates. Denta9-THC and Delta8-THC have been shown both in vitro in a rat liver coenzyme A fortified microsomal system and in vivo in rats to conjugate to fatty acids. Codeine and phencyclidine have also been shown to conjugate to fatty acids in vitro and will be studied in vivo in this proposed program. These in vitro and in vivo studies will be extended to other drugs of abuse such as cocaine, amphetamine, STP (2,5-dimethoxy-4 methylaphetamine), mescaline, Valium (diazepam) and phenobarbital. The drugs will be tested in vivo initially in rats and then in a larger animal such as the dog. Using DeltaTHC, codeine and PCP as representative abused drugs we will also determine if there is substantial rat tissue accumulation from their chronic and prolonged use. A primary objective is to determine if these fatty acid conjugates are themselves pharmacologically active or if the conjugates must be hydolyzed before activity takes place. This evaluation will be made by comparing effects of conjugated and nonconjugated drugs after intracisternal or intravenous injections in rats on behavioral activity and certain neurochemical parameters. By also measuring the concentrations of conjugated and nonconjugated radioactive drugs in the brain, and possibly the liver, after injections of the radioactive drug conjugates we can determine whether the conjugates or their hydrolyzed products are primarily responsible for the pharmacologic activity. Another objective is to determine if these fatty acid conjugated drugs retained in the body might be depleted by the use of therapeutic clearing agents such as heparin, bile salts or lecithin. We have shown that I.V. injections of these compounds depleted fatty acid conjugated DDT metabolites from their liver and spleen storage depots.